What does hepatocellular carcinoma provoke?

There are many known carcinogens that can cause tumors in animals in experiments, but their role in the development of tumors in humans has not been established. Such carcinogens include beta-dimethylaminoazobenzene (yellow dye), nitrosamines, aflatoxin, and ragwort alkaloids.

The process of carcinogenesis from initiation to progression and development of clinical manifestations has many stages. The carcinogen binds to DNA by covalent bonds. Cancer development depends on the ability of the host cells to repair DNA or on tolerance to carcinogenesis.

Association with liver cirrhosis

Cirrhosis, regardless of its etiology, can be considered a precancerous condition. Nodular hyperplasia progresses to cancer. Hepatocyte dysplasia, which is manifested by an increase in their size, nuclear polymorphism, and the presence of multinucleated cells, affects groups of cells or entire nodes and can be an intermediate stage of tumor development. Dysplasia is found in 60% of patients with hepatocellular carcinoma against the background of liver cirrhosis and only in 10% of patients with hepatocellular carcinoma without cirrhosis. In cirrhosis with high proliferative activity of hepatocytes, there is a higher risk of liver cancer. In addition, carcinogenesis can be associated with a genetic defect of a certain clone of cells.

Primary liver tumors

	Benign	Malignant
Hepatocellular	Adenoma	Hepatocellular carcinoma Fibrolamellar carcinoma Hepatoblastoma
Biliary	Adenoma Cystadenoma Papillomatosis	Cholangiocarcinoma Mixed hepatic cholangiocellular carcinoma Cystadenocarcinoma
Mesodermal	Hemangioma	Angiosarcoma (hemangioendothelioma) Epithelioid hemangioendothelioma Sarcoma
Others	Mesenchymal hamartoma Lipoma Fibroma

Prevalence of primary liver cancer worldwide

Geographical area	Frequency per 100,000 males per year
Group 1
Mozambique	98.2
China	17.0
South Africa	14.2
Hawaii	7.2
Nigeria	5.9
Singapore	5.5
Uganda	5.5

Group 2
Japan	4.6
Denmark	3.4
Group 3
England and Wales	3.0
USA	2.7
Chile	2.6
Sweden	2.6
Iceland	2.5
Jamaica	2,3
Puerto Rico	2.1
Colombia	2.0
Yugoslavia	1.9

In one study of 1073 patients with hepatocellular carcinoma, 658 (61.3%) also had cirrhosis. However, 30% of African patients with hepatitis B-associated hepatocellular carcinoma did not have cirrhosis. In the UK, approximately 30% of patients with hepatocellular carcinoma did not develop cirrhosis; survival in this group of patients was comparatively high.

There are significant geographical differences in the incidence of cancer among patients with cirrhosis. The incidence of this combination is particularly high in South Africa and Indonesia, where cancer develops in more than 30% of patients with cirrhosis, while in India, the UK and North America the incidence of cirrhosis and liver cancer is approximately 10-20%.

Connection with viruses

In viral liver disease, hepatocellular carcinoma develops against the background of chronic hepatitis and cirrhosis. Almost all patients with virus-associated hepatocellular carcinoma have concomitant cirrhosis. Necrosis and increased mitotic activity of hepatocytes contribute to the development of regenerative nodes, which under certain conditions leads to hepatocyte dysplasia and cancer development. Although in most cases cancer is preceded by nodular regeneration and cirrhosis, the tumor can also develop without concomitant cirrhosis. In such cases, by analogy with chronic marmot hepatitis (caused by a representative of the hepadnavirus family, which is close to the hepatitis B virus), necrosis and inflammation are necessary conditions for the development of cancer.

Link to Hepatitis B Virus

According to world statistics, the prevalence of HBV carriage correlates with the incidence of hepatocellular carcinoma. The highest incidence of hepatocellular carcinoma is observed in countries with the largest number of HBV carriers. It has been shown that the risk of hepatocellular carcinoma in HBV carriers is higher than in the population. The etiologic role of other representatives of the hepadnavirus family, such as the marmot hepatitis virus, has been proven in the development of hepatocellular carcinoma. HBV DNA is found in the tissue of hepatocellular carcinoma.

Carcinogenesis is a multistage process involving both the virus and the host organism. The end result of this process is disorganization and restructuring of hepatocyte DNA. In hepatitis B, the virus integrates into the host chromosomal DNA, but the molecular mechanism of the carcinogenic effect of HBV remains unclear. Integration is accompanied by chromosomal deletions and translocations that affect cell growth and differentiation (insertional mutagenesis). However, the deletions do not correspond to the sites of viral DNA integration, and in 15% of cancer cases, viral genome sequences are not detected in tumor tissue. It has been shown that the integration of HBV DNA into the host genome is not accompanied by either increased expression of a specific proto-oncogene or deletions of a specific region of the genome carrying a potential antioncogene. The nature of integration into the host cell genome is not constant, and the viral genome in different patients can integrate into different regions of tumor cell DNA.

HBV X-antigen is considered a transactivator, increasing the rate of oncogene transcription.

The HBV envelope pre-S protein can accumulate in sufficient toxic amounts to cause tumor development. Increased production of HBV pre-S protein in transgenic mice leads to severe liver inflammation and regeneration with subsequent tumor development. Dysregulation of HBV envelope protein expression may result from integration into host cell DNA.

Integration of HBV DNA results in translocation of tumor suppressor genes on chromosome 17. Thus, tumor suppressor genes, such as the p53 oncogene on chromosome 17, may play an important role in HBV-dependent hepatocarcinogenesis. Transforming growth factor-a (TGF-a) is overexpressed in 80% of patients with hepatocellular carcinoma. It may act as a cofactor. Histochemical studies show that TGF-a is localized in the same hepatocytes as HBsAg, but is absent from tumor cells.

The most significant precancerous condition is chronic hepatitis B with outcome in cirrhosis. HBV leads to the development of cancer through integration, transactivation, mutations of tumor suppressor genes and increase in TGF-a levels.

In HBsAg carriers infected with HDV, hepatocellular carcinoma is less common, possibly due to the suppressive effect of HDV.

Link to Hepatitis C Virus

There is a clear relationship between the incidence of HCV infection and the prevalence of hepatocellular carcinoma. In Japan, anti-HCV antibodies are detected in the serum of most patients with hepatocellular carcinoma, and approximately half of the cases have a history of blood transfusions. A clear correlation between the incidence of hepatocellular carcinoma and HCV is also observed in Italy, Spain, South Africa, and the United States. The role of HCV in the development of hepatocellular carcinoma is small in regions endemic for HBV infection, such as Hong Kong. The results of epidemiological studies have been influenced by the introduction of more accurate diagnostic methods for HCV infection than first-generation tests. Thus, the incidence of HCV infection in hepatocellular carcinoma in South Africa was 19.5% rather than 46.1%. In the United States, 43% of patients with hepatocellular carcinoma (HBsAg-negative) have anti-HCV detected using second-generation test systems or HCV RNA in serum and liver. HCV appears to play a more important etiologic role in the development of hepatocellular carcinoma than HBV. The incidence of hepatocellular carcinoma among patients with anti-HCV is 4 times higher than in HBsAg carriers. The development of hepatocellular carcinoma in HCV infection does not depend on the genotype of the virus.

The low incidence of HCV-associated hepatocellular carcinoma in the United States compared to Japan is related to the age of patients. Hepatocellular carcinoma develops only 10-29 years after infection. In Japan, HCV infection probably occurred mainly in early childhood through injections using non-sterile syringes. Americans were infected mainly in adulthood (drug addiction, blood transfusion), and hepatocellular carcinoma did not have time to develop during their lifetime.

Unlike HBV, HCV is an RNA-containing virus, lacks the enzyme reverse transcriptase, and is unable to integrate into the host cell genome. The process of hepatocellular carcinoma development is unclear; it apparently occurs against the background of cirrhotic transformation of the liver. However, the HCV genome can be detected in the tumor and surrounding liver tissue of these patients.

There may be an interaction between HBV and HCV in the development of hepatocellular carcinoma, since in patients with HCV and HBV co-infection (HBsAg-positive), hepatocellular carcinoma develops more often than in patients with only anti-HCV.

HCV carriers, like HBV carriers, should be regularly screened for hepatocellular carcinoma using ultrasound and serum alpha-fetoprotein (alpha-FP) levels.

Relationship with alcohol consumption

In Northern Europe and North America, the risk of developing primary hepatocellular carcinoma is four times higher among alcoholics, especially the elderly. They always show signs of cirrhosis, and alcohol itself is not a liver carcinogen.

Alcohol may be a cocarcinogen of HBV. Hepatitis B markers are often detected in patients with alcoholic cirrhosis complicated by hepatocellular carcinoma. Alcohol-stimulated enzyme induction may enhance the conversion of cocarcinogens to carcinogens. Alcohol may also stimulate carcinogenesis due to immunosuppression. Alcohol inhibits carcinogen-mediated DNA alkylation.

In hepatocellular carcinoma in patients with alcoholic cirrhosis, HBV DNA is sometimes found embedded in the DNA of degenerated hepatocytes. However, hepatocellular carcinoma can develop in alcoholics even in the absence of HBV infection (current or previous).

Mycotoxins

The most important mycotoxin is aflatoxin, produced by the mold fungus Aspergillus flavis. It has a pronounced carcinogenic effect in rainbow trout, mice, guinea pigs, and monkeys. There are interspecies differences in sensitivity to the carcinogenic effect of aflatoxin. Aflatoxin and other toxic substances contained in mold can easily get into food products, in particular, groundnuts (peanuts) and grain crops, especially when they are stored in tropical conditions.

A positive correlation between dietary aflatoxin levels and the incidence of hepatocellular carcinoma has been reported in various parts of Africa. Aflatoxin may act as a cocarcinogen in viral hepatitis B.

Studies in Mozambique, South Africa and China have found mutations in the tumor suppressor gene p53 that have been linked to elevated levels of aflatoxin in food. In the UK, where aflatoxin exposure is low, these mutations were rare in liver cancer patients.

Race and Gender

There is no evidence of a role for genetic predisposition in the development of hepatocellular carcinoma.

Worldwide, hepatocellular carcinoma occurs in men three times more often than in women. This can be partly explained by the higher frequency of HBV carriage in men. Increased expression of androgen receptors and suppression of estrogen receptors on tumor cells are possible. The biological significance of this phenomenon is unknown.

The role of other factors

Hepatocellular carcinoma rarely complicates the course of autoimmune chronic hepatitis and liver cirrhosis.

Aflatoxin consumption and the incidence of hepatocellular carcinoma

Country	Terrain	Aflatoxin consumption, ng/kg per day	Frequency of HCC per 100 thousand people per year
Kenya	Highlands	3.5	1,2
Thailand	City of Sonkla	5.0	2.0
Swaziland	Steppe (high above sea level)	5.1	2,2
Kenya	Medium height mountains	5.9	2.5
Swaziland	Steppe (average altitude above sea level)	8.9	3.8
Kenya	Low mountains	10.0	4.0
Swaziland	Lebombo Hills	15.4	4.3
Thailand	Ratchaburi city	45.6	6.0
Swaziland	Steppe (low above sea level)	43.1	9.2
Mozambique	The city of Inhambane	222.4	13.0

In Wilson's disease and primary biliary cirrhosis, hepatocellular carcinoma is also very rare.

Hepatocellular carcinoma is a common cause of death in patients with hemochromatosis. It is common in alpha ₁ -antitrypsin deficiency, glycogen storage disease type I, and porphyria cutanea tarda.

Hepatocellular carcinoma may be a complication of massive immunosuppressive therapy in patients with a kidney transplant.

Clonorchiasis may be complicated by hepatocellular carcinoma and cholangiocellular carcinoma.

There is no established link between schistosomiasis and liver cancer.

In Africa and Japan, hepatocellular carcinoma is associated with membranous obstruction of the inferior vena cava.